This proposal advocates the function of glial cell astrocytic acetaldehyde dehydrogenase 2 (ALDH2) as the first line neuroprotective defense mechanisms in the brain from alcohol abuse. Neutralization of reactive acetaldehyde by ALDH2 promotes the key initial protective biochemical mechanisms in alcohol abuse. The statement is supported by our recent findings that activation of NADPH oxidase and inducible nitric oxide synthase by acetaldehyde increases the levels of reactive oxygen species and nitric oxide in primary human neurons. To prevent the action of acetaldehyde as transducer for oxidative stress, a therapeutic stabilization of astrocytic ALDHs by acetyl-L-carnitine (ALC) is an innovative approach, which has not been studied so far. This protective mechanism of astrocytes is arisen from the fact that ALDHs are genuine antioxidants that can balance oxidant and antioxidant levels in alcohol stress. Our proposal is that stabilization of the inherent astrocytic ALDH2 protein in the brain shields the neurons from adverse effects of alcohol and acetaldehyde toxicity. Therefore, astrocytes are active defenders of neurons from the deleterious effects of alcohol. The central hypothesis of the proposal is that effective detoxification of acetaldehyde by ALC-stabilized astrocytic ALDH2 can prevent the oxidative damage and neurotoxicity. We propose to investigate the protective mechanisms by using primary mice and human astrocytes and neuronal co-cultures as in vitro system and chronic ethanol liquid diets feeding as our animal model. Success of the project will impact knowledge gap in unraveling the cellular and biochemical mechanisms of alcohol effects in neurobiology and health care. PUBLIC HEALTH RELEVANCE: The relevance of the proposal addresses the novelty that astrocytes are the active defenders of neurons from the deleterious effects of alcohol by virtue of their inherent ALDH2 function. Stabilization of astrocytic ALDH2 protein in brain shields the sensitive neurons from the adverse effects of alcohol toxicity. Therefore, astrocytes are the active defenders of the brain and the success of the proposal has a huge potential impact for prevention of many alcohol-related neurological disorders in health care.